The association between air pollution and lung cancer in ...€¦ · The association between air pollution and lung cancer in the North West of Adelaide: a case control study and

The association between air pollution and lung cancer

in the North West of Adelaide: a case control study

and air quality monitoring

Melissa Jayne Whitrow

Department of Medicine and Department of Public Health

Faculty of Health Science

The University of Adelaide

July 2004

1

Table of Contents

1. Chapter 1 Introduction .............................................................................................. 25

1.1. Lung Cancer........................................................................................................... 29

1.1.1. Lung Cancer Demographics........................................................................... 29

1.1.2. Lung Cancer in Australia ............................................................................... 33

1.1.3. Aetiology........................................................................................................ 37

1.2. North Western Metropolitan Adelaide................................................................ 38

1.2.1. Lung Cancer in the North West...................................................................... 40

1.2.2. Industry in the North West ............................................................................. 40

1.2.3. Ambient Air Quality in the NW..................................................................... 49

2. Chapter 2 Review of the Literature .......................................................................... 51

2.1. Lung Cancer Histology.......................................................................................... 52

2.1.1. Lung Cancer Classification ............................................................................ 53

2.2. Lung Carcinogen Classifications.......................................................................... 56

2.2.1. Lung Carcinogens .......................................................................................... 56

2.3. The Origins of the Association between Air Pollution and Lung Cancer ........ 59

2.4. A review of the Epidemiological Evidence for a Causal Relationship between

Environmental Exposure to Carcinogens (Air Pollution) and Lung Cancer 59

2.4.1. Literature Review Methodology .................................................................... 60

2.4.2. Results of the Literature Review.................................................................... 61

2

2.4.2.1. Environmental Exposure Classification.................................................. 71

2.4.2.2. Strength of Association ........................................................................... 71

2.4.2.3. Consistency ............................................................................................. 75

2.4.2.4. Specificity and confounder adjustment ................................................... 76

2.4.2.5. Temporality ............................................................................................. 80

2.4.2.6. Dose Response ........................................................................................ 80

2.4.2.7. Biological Plausibility/Coherence........................................................... 81

2.4.2.8. Analogy ................................................................................................... 82

2.4.3. Discussion of the Literature Review Findings ............................................... 82

2.5. Air Pollution and Lung Cancer in Australia....................................................... 85

2.6. Aims and Hypothesis ............................................................................................. 86

3. Chapter 3 Methodology ............................................................................................. 89

3.1. Study Design........................................................................................................... 89

3.1.1. Cases............................................................................................................... 89

3.1.1.1. Sample..................................................................................................... 89

3.1.1.1.1. Inclusion Criteria ........................................................................... 89

3.1.1.1.2. Exclusion Criteria .......................................................................... 90

3.1.1.2. Sampling Frame ...................................................................................... 90

3.1.2. Controls .......................................................................................................... 91

3.1.2.1. Sample..................................................................................................... 91

3

3.1.2.1.1. Inclusion Criteria ........................................................................... 91

3.1.2.1.2. Exclusion Criteria .......................................................................... 91

3.1.2.2. Sampling Frame ...................................................................................... 92

3.1.2.2.1. Selection ........................................................................................ 92

3.1.3. Matching......................................................................................................... 93

3.1.4. Subject Recruitment ....................................................................................... 94

3.2. Ethics Approval ..................................................................................................... 98

3.2.1. Informed Consent........................................................................................... 98

3.3. The Design and Development of a Questionnaire to Investigate Lung

Carcinogen Exposure in a Case Control Study ................................................ 99

3.3.1. Identification of Potential Confounders ......................................................... 99

3.3.2. Format of Questionnaire............................................................................... 103

3.3.3. Pilot of Questionnaire................................................................................... 105

3.3.4. Method of Data Collection........................................................................... 106

3.3.5. Interviewer Training..................................................................................... 107

3.4. Environmental Exposure Assessment and Quantification .............................. 107

3.4.1.1. Calculation of Distance from Industry within the Study Geographical

Area ....................................................................................................... 113

3.4.1.2. Calculation of Angle of each Residence from each Industry................ 115

3.4.1.3. Calculation of Exposure Based on Wind Direction .............................. 116

3.4.1.4. Calculation of a Final Exposure Score.................................................. 118

4

3.4.1.5. Validity.................................................................................................. 121

3.4.1.6. Reliability.............................................................................................. 121

3.4.2. Exposure Assessment Outside of the Study Area ........................................ 121

3.4.2.1. Definition of Exposed ........................................................................... 121

3.4.2.2. Validity.................................................................................................. 124

3.4.2.3. Reliability.............................................................................................. 124

3.4.2.4. Inclusion in Analysis............................................................................. 124

3.5. Tobacco Exposure Quantification...................................................................... 125

3.5.1. Direct Smoking ............................................................................................ 125

3.5.1.1. Cigars and Tobacco Pipes ..................................................................... 128

3.5.2. Environmental Tobacco Smoking................................................................ 128

3.5.3. Reliability ..................................................................................................... 130

3.5.4. Validity......................................................................................................... 130

3.6. Occupational Exposure Assessment and Quantification ................................. 130

3.6.1. The Occupational Hygiene Panel ................................................................. 130

3.6.2. Occupational Data Collected from Subjects for Exposure Assessment....... 132

3.6.3. Levels of Exposure Assessed ....................................................................... 132

3.6.4. Levels of Exposure....................................................................................... 133

3.6.5. Occupational Hygiene Panel Output ............................................................ 136

3.6.6. Inclusion in Analysis.................................................................................... 137

3.6.7. Quantification of Exposure Levels in the Analysis...................................... 137

5

3.6.7.1. Calculation of Dose Years .................................................................... 138

3.6.8. Reliability ..................................................................................................... 139

3.6.9. Validity......................................................................................................... 139

3.7. Quantification of Other Potential Confounders ............................................... 140

3.7.1. Hobbies......................................................................................................... 140

3.7.2. Socioeconomic Status .................................................................................. 141

3.7.3. Family History.............................................................................................. 141

3.8. Substudy: A Comparison of the Responses from Controls and their Next of

Kin (NOK).......................................................................................................... 142

3.8.1. Sample.......................................................................................................... 142

3.8.2. The Tool ....................................................................................................... 142

3.8.3. Classification................................................................................................ 143

3.8.4. Substudy Analysis ........................................................................................ 143

3.9. Statistics ................................................................................................................ 144

3.9.1. Sample Size Calculation............................................................................... 144

3.9.2. Data Entry and Storage ................................................................................ 144

3.9.3. Analysis........................................................................................................ 145

3.10. Distribution of Case Control Study Results ...................................................... 146

3.11. Ambient Air Sampling Methodology ................................................................. 147

3.11.1. Monitoring Locations................................................................................... 148

3.11.2. Sampling Duration and Timing.................................................................... 151

6

3.11.3. Field Work.................................................................................................... 152

3.11.4. Meteorological Measurements ..................................................................... 155

3.11.5. Air Quality Monitoring Analysis ................................................................. 155

4. Chapter 4 Results ..................................................................................................... 156

4.1. Sample Demographics ......................................................................................... 156

4.1.1. Study Participants......................................................................................... 156

4.1.2. Participants versus Non-participants............................................................ 157

4.1.2.1. Cases ..................................................................................................... 157

4.1.2.1.1. Differential Participation Rate for Age and Gender .................... 160

4.1.2.1.2. Distance from Industry ................................................................ 160

4.1.2.2. Controls ................................................................................................. 161

4.1.2.2.1. Differential Response Rate for Age and Gender ......................... 162

4.1.2.3. Distance from Industry.......................................................................... 164

4.1.3. Occupational Hygiene Panel Agreement ..................................................... 165

4.1.4. Next of Kin Agreement ................................................................................ 166

4.2. Univariate Analysis.............................................................................................. 167

4.2.1. Socio-economic Status ................................................................................. 167

4.2.2. Residential Exposure within the Study Area................................................ 169

4.2.3. Residential Exposure outside of the Study Area.......................................... 173

4.2.4. Cigarette Smoking........................................................................................ 174

7

4.2.5. Environmental Tobacco Smoke (ETS) ........................................................ 177

4.2.6. Occupational Exposure to Lung Carcinogens.............................................. 178

4.2.7. Hobbies......................................................................................................... 183

4.2.8. Family History of Lung Cancer ................................................................... 184

4.3. Bivariate Analysis ................................................................................................ 185

4.3.1. Subject Demographics.................................................................................. 186

4.3.2. Socio-economic Status ................................................................................. 186

4.3.3. Residential Exposure.................................................................................... 188

4.3.4. Cigarette Smoking........................................................................................ 192

4.3.5. Environmental Tobacco Smoke (ETS) ........................................................ 194

4.3.6. Occupational Exposure to Lung Carcinogens.............................................. 195

4.3.7. Hobbies......................................................................................................... 196

4.3.8. Family History of Lung Cancer ................................................................... 198

4.4. Multivariate Analysis .......................................................................................... 199

4.5. Post hoc Analysis.................................................................................................. 208

4.5.1. Post hoc Multivariate Analysis .................................................................... 209

4.6. Air Quality Monitoring ....................................................................................... 218

5. Chapter 5 Discussion................................................................................................ 224

5.1. Limitations of the Case Control Study .............................................................. 226

5.1.1. Bias............................................................................................................... 226

8

5.1.2. Misclassification........................................................................................... 228

5.1.2.1. Subject Misclassification ...................................................................... 228

5.1.2.2. Exposure Misclassification ................................................................... 228

5.1.2.3. Environmental exposure misclassification............................................ 230

5.1.2.4. Occupational exposure misclassification .............................................. 231

5.1.3. Significance of limitations on results ........................................................... 245

5.2. The Present Results in Context with the Literature......................................... 248

5.3. Future Epidemiological Research ...................................................................... 261

5.4. Discussion of Ambient Air Quality .................................................................... 263

5.5. Summary .............................................................................................................. 267

6. Chapter 6 Appendices .............................................................................................. 269

7. Chapter 7 References ............................................................................................... 334

9

Index to Tables

Table 1-1: Age standardised incidence rate of lung cancer per 100 000 by level of country

development8....................................................................................................... 30

Table 1-2: Key Industry Identified as having the Potential to Emit Lung Carcinogens, and

Operational in the Study Area (North West Suburbs of Adelaide) in the period

1970 to 2000 ....................................................................................................... 46

Table 2-1: Features of each Lung Cancer Cell Type ............................................................. 54

Table 2-2: Carcinogen Classifications Employed by IARC37 ............................................... 56

Table 2-3: Known (1) or Probable (2a) Respiratory Carcinogens and their Potential

Sources38 39 .......................................................................................................... 57

Table 2-4: Adjustments for the Confounding Effects of Smoking and Occupation.............. 63

Table 3-1: Lung Cancer Risk Factors .................................................................................. 100

Table 3-2: Assessment of Questionnaires............................................................................ 104

Table 3-3: Studies using dispersion modelling to determine the relationship between

proximity to industry and adverse health effects .............................................. 109

Table 3-4: X and Y Coordinates for the 6 Key Industries in the North West...................... 114

Table 3-5: Calculation of the Percentage of Time the Wind Blows ± 15˚ around each

Angle from North in 10˚ Increments................................................................. 119

Table 3-6: List of Industry Types Identified by the Occupational Hygiene Panel as Likely

to Emit Lung Carcinogens ................................................................................ 122

Table 3-7: Tobacco Smoking - Data collected and its Inclusion in the Analysis ................ 126

Table 3-8: Environmental Tobacco Smoke - Data Collected and its Inclusion in the

Analysis............................................................................................................. 129

Table 3-9: Contemporary Health Based Daily (8hr) Occupational Exposure Guidelines... 134

10

Table 3-10: Percentage of Exposure Guidelines Assigned to Each Level of Exposure

(Average Daily Exposure) ................................................................................ 135

Table 3-11: Scores Assigned to Each Level of Occupational Exposure ............................. 138

Table 3-12: Potential Lung Carcinogen Exposures for Reported Hobbies as Determined by

the Occupational Hygiene Panel ....................................................................... 141

Table 3-13: Interpretation of the Kappa Statistic................................................................. 144

Table 3-14: Lung Carcinogens (IARC rating 1* and 2A**) and potential sources in North

West of Adelaide............................................................................................... 147

Table 4-1: Age and Gender of Study Participants ............................................................... 156

Table 4-2: Case Participation Rates..................................................................................... 158

Table 4-3: Distance from Industry* (kms) of Current Residence of Participating and Non-

Participating Cases............................................................................................ 161

Table 4-4: Control Participation Rates ................................................................................ 162

Table 4-5: Distance from Industry* (kms) of current Residence of Participating and Non-

Participating controls ........................................................................................ 164

Table 4-6: Inter-rater Reliability of Hygiene Panel Exposure Scores Measured by Kappa 165

Table 4-7: Test-Retest Analysis of Hygiene Panel Exposure Scores Measured by weighted

Kappa (n=30 pairs) ........................................................................................... 166

Table 4-8: Indices of Socio-economic Status for Cases and Controls................................. 168

Table 4-9: A Comparison between Cases and Controls of Residential Scores# for each

Identified Industry............................................................................................. 170

Table 4-10: A Comparison between Cases and Controls of Residential Exposure* outside

of the Study Area .............................................................................................. 173

Table 4-11: Comparison of the Cigarette Smoking Habits of Cases and Controls‡ ............ 174

Table 4-12: Environmental Tobacco Smoke (ETS) Exposure by Cases and Controls........ 177

11

Table 4-13: Occupational Exposure to each Lung Carcinogen for Cases and Controls -

Jockel equation method*(units are exposure years) ......................................... 179

Table 4-14: Duration of Probable or Possible Occupational Exposure to each Lung

Carcinogen for Cases and Controls (units are years of exposure) .................... 181

Table 4-15: Hobby Participation for Cases and Controls (yes or no).................................. 183

Table 4-16: Number of Family Members* with Lung Cancer Diagnosis for Cases and

Controls............................................................................................................. 184

Table 4-17: Bivariate Analysis - Odds Ratio for Subject Demographics with Adjustment

for Matching...................................................................................................... 186

Table 4-18: Bivariate Analysis - Odds Ratios for Socioeconomic Status Variable with

Adjustment for Matching.................................................................................. 187

Table 4-19: Bivariate Analysis - Odds Ratio for Residential Exposure Scores# with

Adjustment for Matching.................................................................................. 189

Table 4-20: Bivariate Analysis - Odds Ratio for Duration of Residential Exposure*

outside of the North West of Adelaide, with Adjustment for Matching........... 192

Table 4-21: Bivariate analysis - Odds Ratio for Smoking (as defined by durations in years,

average cigarettes per day or pack years) with Adjustment for Matching........ 193

Table 4-22: Bivariate Analysis - Odds Ratio for Duration of Exposure (yrs) to

Environmental Tobacco Smoke (ETS) at home or work with adjustment for

matching............................................................................................................ 194

Table 4-23: Bivariate Analysis - Odds Ratio for greater than or equal to 1 year of Probable

or Possible Occupational Exposure with Adjustment for Matching................. 195

Table 4-24: Bivariate Analysis - Odds Ratio for Participation (greater than or equal to 1

year) in Mechanical, Pottery or House Renovation Hobbies with Adjustment

for Matching...................................................................................................... 197

12

Table 4-25: Bivariate Analysis - Odds Ratio for the Number of Family Members* who

have been Diagnosed with Lung Cancer with Adjustment for Matching......... 198

Table 4-26: Final Multivariate Model of Case Control Study Data - Significant Factors

(p≤0.05) and Residential Exposure* to Adelaide Brighton Cement................. 200


(p≤0.05) and Residential Exposure* to CSR .................................................... 201


(p≤0.05) and Residential Exposure* to Finsbury.............................................. 202


(p≤0.05) and Residential Exposure* to Penrice Soda Products........................ 203


(p≤0.05) and Residential Exposure* to James Hardies..................................... 204


(p≤0.05) and Residential Exposure* to Torrens Island Power Station ............. 205


(p≤0.05) and the Composite† Residential Exposure* Score............................. 206

Table 4-33: Post hoc Multivariate Analysis - Significant Factors (p≤0.05) and Adjusted

Residential Exposure* to Adelaide Brighton Cement ...................................... 210

Table 4-34: Post hoc Multivariate Analysis - Significant factors (p≤0.05) and Adjusted

Residential Exposure* to CSR.......................................................................... 211


Residential Exposure* to Finsbury ................................................................... 212


Residential Exposure* to James Hardies .......................................................... 213

13


Residential Exposure* to Penrice Soda Products ............................................. 214


Residential Exposure* to Torrens Island Power Station................................... 215

Table 4-39: Post hoc Multivariate Analysis - Significant Factors (p≤0.05) and the

Adjusted Composite† Residential Exposure* Score......................................... 216

Table 4-40: Ambient Concentrations of Respiratory Carcinogens in the North West of

Adelaide ............................................................................................................ 219

Table 5-1: Common Sources of Misclassification in Community-based Case Control

Studies of Occupational Exposures .................................................................. 233

Table 5-2: Results for Smoking and Lung Cancer Relationship from European Case

Control Study - OR(95%CI)80 .......................................................................... 248

Table 5-3: Comparison of the Epidemiological Design Strengths of the 5 Studies

Identified in Chapter 2, and the Present Case Control Study ........................... 252

14

Index to Figures

Figure 1-1: Lung Cancer Incidence1 and Industry Location in the North West of

Metropolitan Adelaide from 1992 to 1995. ........................................................ 26

Figure 1-2: Aerial View of the Lefevre Peninsula5 ............................................................... 27

Figure 1-3: World Male Lung Cancer Incidence and Mortality Rates by Region (Age

standardised estimates for 2000 based on 3-5yrs earlier and adjusted for

increase in population8 )...................................................................................... 31

Figure 1-4: World Female Lung Cancer Incidence and Mortality Rates by Region (Age

standardised estimates for 2000 based on 3-5 years earlier and adjusted for

increase in population8)....................................................................................... 32

Figure 1-5: Australian Male Cancer Mortality Rate by Type of Cancer (Age standardised,

per 100 000, estimates for 2000 based on 3-5yrs earlier and adjusted for


Figure 1-6: Australian Female Cancer Mortality Rate by Type of Cancer (Age

standardised, per 100 000, estimates for 2000 based on 3-5 yrs earlier and

adjusted for increase in population8)................................................................... 35

Figure 1-7: Australian Age Standardised Rates of Lung Cancer Mortality (Adjusted for


Figure 1-8: Aerial View of the Port River21 .......................................................................... 41

Figure 1-9: The Torrens Island Power Station23 .................................................................... 43

Figure 1-10: Aerial View of Adelaide Brighton Cement25 .................................................... 44

Figure 2-1: Two Levels of Tumour Differentiation............................................................... 55

Figure 2-2: Fixed Effects Forest Plot of Case Control Studies.............................................. 73

Figure 2-3: Strength of Association - Results from Cohort Studies ...................................... 74

Figure 3-1: Stata Do File used for Generation of Random Numbers .................................... 93

15

Figure 3-2: Flow Chart of Lung Cancer Patient Recruitment Protocol ................................. 95

Figure 3-3: Flow Chart of Control Recruitment Protocol...................................................... 96

Figure 3-4: Flowchart of Subject Participation Protocol ....................................................... 97

Figure 3-5: Graphical Representation of the Relationship between Environmental

Exposure and Proximity to Industry from the Literature.................................. 112

Figure 3-6: Equation utilised to represent residential exposure to a point source ............... 113

Figure 3-7: Pythagorus Theorem of a Right Angle Triangle............................................... 114

Figure 3-8: Application of Pythagoras Theory .................................................................... 115

Figure 3-9: Method Utilised to Calculate Occupational Dose Years per Carcinogen......... 138

Figure 3-10: Location of Air Monitoring Sampling Sites within the North West of

Adelaide ............................................................................................................ 149

Figure 3-11: Photograph of Monitoring Site 2 - Birkenhead............................................... 150

Figure 3-12: Photograph of Monitoring Site 4 - Mile End (in Environmental Protection

Authority Cage) ................................................................................................ 151

Figure 4-1: Case Participation Rates by Gender and Age Group ........................................ 159

Figure 4-2: Control Participation Rates by Gender and Age Group.................................... 163

Figure 4-3: PM2.5 Diurnal Variation, example from Site 1 ................................................ 223

16

Index to Appendices

Appendix 1: Copy of standard information letter to recruit potential cases ........................ 270

Appendix 2: Information letter to the Next of Kin of a deceased case when the diagnosing

Doctor had already approached them by phone................................................ 273

Appendix 3: Original information letter to the Next of Kin (NOK) of a deceased case,

when the diagnosing doctor had been unable to speak to the NOK by phone

prior to the letter................................................................................................ 276

Appendix 4: "Calling a Patient" Information Sheet Provided to Recruiting Doctors.......... 279

Appendix 5: "Calling the Next of Kin of a Patient" Information Sheet Provided to

Diagnosing Doctors .......................................................................................... 280

Appendix 6: Original information letter to controls ............................................................ 281

Appendix 7: Script for Follow Up Calls to Non-responding Potential Control Subjects.... 284

Appendix 8: Example of a Flyer Sent to Recruiting Doctors to Encourage Further Case

Recruitment and Completion of the Study........................................................ 285

Appendix 9: Examples of Articles in the Print Media about the Case Control Study......... 286

Appendix 10: Copies of Ethics Approval Letters from Adelaide Metropolitan Hospitals.. 287

Appendix 11: The Queen Elizabeth Hospital Research and Ethics Committee Consent

Form Utilised in this Study ............................................................................... 294

Appendix 12: Part 'a' of the Data Collection Process utilised to Enhance Recall Prior to the

Structured Interview.......................................................................................... 295

Appendix 13: The Structured Questionnaire used to elicit Lifetime Information on Risk

Factors Relevant to Lung Cancer Diagnosis..................................................... 298

Appendix 14: Booklet Used to Record Data Collected at Interview................................... 319

Appendix 15: Example of Occupational Information Provided to Occupational Hygiene

Panel for Exposure Assessment ........................................................................ 327

17

Appendix 16: Occupational Hygiene Panel Output Sheet................................................... 328

Appendix 17: Survey of Members of the Australian Institute of Occupational Hygienists

to Determine the Percentage of Exposure Guidelines Assigned to Each

Category of Occupational Exposure ................................................................. 329

Appendix 18: Questionnaire used for the Next Of Kin Substudy ....................................... 331

Appendix 19: Information Letter Distributed to Participating Subjects to Summarise the

Study Results .................................................................................................... 333

18

Abstract

Some suburbs within North West (NW) metropolitan Adelaide have lung cancer mortality

up to twice that expected from state averages. Previous international research

investigating high lung cancer rates in similar shared industrial and residential areas have

had inconsistent results. This case control study was conducted to determine whether

residential exposure to industry is a risk factor for lung cancer in NW Adelaide.

Contemporary ambient air monitoring was undertaken as an indicator of future respiratory

health risk.

142 lung cancer patients and 415 age, gender matched population controls were

interviewed utilising an event history calendar. Lifetime exposure indices were calculated

for cigarette smoking, passive smoking, occupation, air pollution (residential proximity to

industry) and hobbies. Data was analysed utilising chi-squared and conditional logistic

regression. Ambient carcinogens and fine particulates with potential industrial sources in

the region were monitored in five locations.

In the final multivariate model leaving school early, pack-years of cigarettes and not living

in close proximity to the power station or light industrial area were statistically significant

risk factors for lung cancer. A composite score of residential exposure to all industries

was not significant. However cautious interpretation is required as it was noted

participating controls resided significantly closer to industry than non-participants.

Average concentrations of ambient carcinogens were within guidelines; however diesel

exhaust particulate and Polycyclic Aromatic Hydrocarbons were elevated at sites in

19

proximity to heavy vehicle traffic. Diurnal variations in PM2.5 included weather and

traffic-related short term peaks, and other peaks potentially related to industrial activity.

Cigarette smoking is likely to be the primary cause of elevated lung cancer mortality in

suburbs of NW Adelaide. The negative effect of residential exposure to two industries

may be due to participation bias. Whilst having more thorough exposure assessment than

previous research, this study may have been limited by low participation rates in cases and

controls. Air monitoring data suggests there is not a significant public health risk at

present; however these results are unlikely to be indicative of historical exposures. Future

public health initiatives to curb high lung cancer mortality in the NW should focus on

smoking prevention and reduction strategies.

20

This work contains no material which has been accepted for the award of any other degree

or diploma in any university or other tertiary institution and, to the best of my knowledge

and belief, contains no material previously published or written by another person, except

where due reference has been made in the text.

I give consent to this copy of my thesis, when deposited in the University Library, being

available for loan and photocopying.

Signed _____________________________________

Date ___________

21

Acknowledgements

This research was funded by a project grant from the National Health and Medical Council

Thank you to my three supervisors, Brian Smith, Louis Pilotto and Dino Pisaniello for

their advice, expertise and support.

I would like to gratefully acknowledge the original research team that initiated the project

concept and secured funding – Brian Smith, Monika Nitschke, Dino Pisaniello, Richard

Ruffin and Janet Hiller.

Thank you to the staff of the Clinical Epidemiology and Health Outcomes Unit for their

friendship and support. Particularly to Pam Selim, Adrian Heard and Jesia Berry for their

assistance with interviewing subjects, and Daniel Field and Crystal Read for assistance

with data entry.

Thank you to Adrian Esterman for assistance with the statistical analysis of the case

control study data.

Thank you to the study subjects who so freely gave their time to be interviewed for this

study.

To my family, in particular Mum, Phil, Denise, Neville and Stacey, thank you for the love,

support and friendship you have provided to me throughout this entire process.

To my partner Damien – I couldn’t have done this without your unwavering support and

love. Thanks for believing in me.

22

Thesis Collaborations

I would like to thank the following people and organisations for their assistance with the

project:

BHP (analysis of diesel air monitoring samples)

CEMSSA – Prof John Terlett (analysis of asbestos air monitoring samples)

Charles Sturt Council (supply of GIS coordinates)

Collaborative Centre in Occupational Health and Safety – University of Adelaide – in

particular Andrew Orfanos for assistance with air quality monitoring and sample analysis

Epidemiology, Flinders Medical Centre – Adrian Esterman (statistical advice), Paul

Hakendorf (Geographical Information System advice)

Environmental Health Branch, Dept of Human Services – David Simon (advice on wind

direction calculations)

Environmental Protection Authority (advice on air quality monitoring protocols and

interpretation of monitoring results)

MPL (loan of air quality monitoring equipment and hygiene panel participation)

Pt Adelaide Enfield Council (supply of GIS coordinates)

South Australian Cancer Registry, Dept of Human Services – David Roder and Colin

Luke (provision of lung cancer patient information to the recruitment hospitals)

Dept of Pathology, The University of Adelaide – Angela Barbour (supply of lung cancer

histology pictures)

23

Publications Arising from this Thesis

Refereed Journals:

Whitrow MJ, Smith BJ, Pilotto LS, Pisaniello DP, Nitschke M (2003). Environmental

exposure to carcinogens causing lung cancer: Epidemiological evidence from the medical

literature. Respirology 8 (4), 513-521

Conference Presentations:

Oral

Whitrow MJ, Pisaniello D, Smith BJ, Pilotto L. Concentration of Fine Particulate Matter

in an Industrial/Residential Adelaide Suburb. Australasian Epidemiological Association

10th Annual Scientific meeting, Sydney, Australia. 2001

Whitrow MJ, Smith BJ, Pilotto L, Nitschke M, Pisaniello D. Environmental Exposure to

Carcinogens Causing Suburban Lung Cancer – Epidemiological Evidence. Royal

Australian College of Physicians Conference, Adelaide, Australia. 2000

24

Conference Presentations: (continued)

Poster

Whitrow MJ, Smith B, Pilotto L, Pisaniello D, Selim P, Esterman, A. High lung cancer

mortality in the North West of Adelaide is Associated with Cigarette Smoking and

Appears Unrelated to Residential Exposure to Industry. American Thoracic Society,

Seattle, USA. 2003

Whitrow MJ, Smith B, Pilotto L, Pisaniello D, Selim P, Esterman, A. High lung cancer

mortality in the North West of Adelaide is Associated with Cigarette Smoking and

Appears Unrelated to Residential Exposure to Industry. Thoracic Society of Australia and

New Zealand Annual Scientific meeting, Adelaide, Australia. 2003

Eli Lilly prize for best presentation on lung cancer

Whitrow MJ, Smith BJ, Pilotto L, Nitschke M, Pisaniello D. Environmental Exposure to

Carcinogens Causing Suburban Lung Cancer – Epidemiological Evidence. Australasian

Epidemiological Assoc. 10th Annual Meeting, Sydney, Australia. 2003

25

1. Chapter 1 Introduction

The South Australian (SA) Social Health Atlas indicates the North Western suburbs of

Adelaide, in particular the Lefevre Peninsula suburbs, have an alarming excess of lung

cancer mortality with standardised mortality ratios ranging up to 236 compared to that

expected from Adelaide metropolitan rates1 (standardised for age and gender).

The North Western suburbs of Adelaide are a residential zone, bound to the West by the

Gulf of St Vincent, to the South and East by dense residential areas, and to the North by

residential homes and vacant land (Figure 1-1). The Port River flows from the North

(dividing off the Lefevre Peninsula) and is the primary shipping port for metropolitan

Adelaide (Figure 1-2). Attracted by access to shipping ports for the transport of goods

into and out of the metropolitan area, since Adelaide was settled the land either side of the

river has been the site of many industries including power plants, cement and soda product

producers and an asbestos factory2. This area has historically housed blue-collar workers,

with many of the residents employed by the factories clustered along the Port River. The

Lefevre Peninsula is characterised by the close proximity of residential homes to large-

scale industry, with often no more than a 2-lane road (approximately 20 metres) dividing

them. Many of these industries, for example a power station, cement works and mineral

building products manufacturer, are licensed by government agencies to carry out

“prescribed” polluting activities permitting the release of a range of emissions, including

lung carcinogens, into the air.

26

Figure 1-1: Lung Cancer Incidence1 and Industry Location in the North West of Metropolitan Adelaide from 1992 to 1995.

Due to the primarily low socio-economic nature of the areas population, the high lung

cancer mortality has been anecdotally attributed to a high prevalence of cigarette smoking.

However this is yet to be proven in an epidemiological study. Only 1 other peer-reviewed

study has been carried out investigating respiratory health in the area3. This cross

sectional survey found high rates of some respiratory health problems (asthma, bronchitis

and emphysema), but more relevantly, found the prevalence of cigarette smoking in the

area to be 27%, significantly higher than the national average derived from the National

Health Survey at a similar period of time4, but with an absolute difference of just 3%.

Taken at face value the doubling of lung cancer mortality in the area seemed unlikely to be

attributable to a 3% increase in smoking prevalence, however the study only used

prevalence of cigarette smoking rather than quantifying smoking dose.

27

Figure 1-2: Aerial View of the Lefevre Peninsula5

28

The following thesis documents an epidemiological study undertaken to investigate

whether residing in close proximity to industry likely to emit lung carcinogens is a

significant risk factor for lung cancer in the NW suburbs of Adelaide. It begins with a

description of the burden of lung cancer worldwide on public health care systems and a

detailed description of the NW suburbs of Adelaide and the relevant lung cancer mortality

figures. Following that is a systematic review of previous international epidemiology

studies investigating the relationship between lung cancer and air pollution. The

methodology of the thesis is described in detail, the results of which are documented in a

series of tables. Finally there are the discussion and conclusions, which summarise the

findings of this research, identifies its limitations, assesses the results in context with

previous published studies, and suggests potential avenues for future research. In parallel

with the epidemiology study, air quality monitoring was undertaken to determine

contemporary concentrations of airborne lung carcinogens in the study area, with the view

to identify the potential for future respiratory health risk.

29

1.1. Lung Cancer

Lung Cancer is the term used to define the uncontrolled growth of malignant cells in the

lung. Diagnosis of lung cancer is through a combination of x-ray, sputum cytology,

bronchoscopy, MRI (magnetic resonance imaging) or CT (computer assisted topography)

chest scan6. Early lung malignancies are usually clinically silent, hence lung cancer is

rarely diagnosed until patients are symptomatic and the tumour is in an advanced stage.

Treatment is by surgery, radiotherapy and/or chemotherapy7. Prognosis with or without

treatment is poor, Non-small-cell tumours have a 50% survival rate 2 years post diagnosis,

and Small-cell tumours have a 1 year prognosis if treated, and 3 month prognosis if not

treated6. The patient prognosis improves slightly if diagnosis is early, whilst the tumour is

still asymptomatic.

1.1.1. Lung Cancer Demographics

Worldwide mortality figures indicate approximately 1.1 million deaths were attributed to

lung or bronchial cancer in 20008. The incidence of lung cancer is greater in more

developed than less developed countries (Table 1-1). Compared to other regions of the

world (Figure 1-3 and Figure 1-4), Australia and New Zealand combined have the 3rd

highest female and 7th highest male incidence rates of lung cancer (age standardised8). As

developed regions, both European and North American countries have consistently

elevated incidence amongst females and males, with North America having the

overwhelmingly highest rates in females (Figure 1-4). In the majority of countries there is

little difference between the incidence and mortality lung cancer figures, illustrating the

poor prognosis for lung cancer patients.

30

Table 1-1: Age standardised incidence rate of lung cancer per 100 000 by level of

country development8

More developed countries Less developed countries

Males 55.62 24.79

Females 15.62 8.44

Lung cancer places a large burden on health care systems around the world. In America

alone lung cancer costs the health system US$8 billion annually9. Canadian estimates are

that the treatment of 1 Non-small-cell lung cancer patient from diagnosis until death is

CDN$19,781, and the corresponding cost for Small-cell is CDN$25,988. The major

component of this expense is hospitalisation9.

31

Figure 1-3: World Male Lung Cancer Incidence and Mortality Rates by Region (Age standardised estimates for 2000 based on 3-5yrs earlier and adjusted for increase in population8 )

0

10

20

30

40

50

60

70

80

Eas

tern A

frica

Midd

le Af

rica

Nor

thern

Afric

a

Sou

thern

Afric

a

Wes

tern A

frica

Car

ibbea

n

Cen

tral A

meric

a

Sou

th Am

erica

Nor

thern

Ame

rica

Eas

tern A

sia

Sou

th-Ea

stern

Asia

Sou

th Ce

ntral

Asia

Wes

tern A

sia

Eas

tern E

urop

e

Nor

thern

Eur

ope

Sou

thern

Eur

ope

Wes

tern E

urop

e

Aus

tralia

/New

Zea

land

Mela

nesia

Micr

ones

ia

Poly

nesia

Region

Rat

e pe

r 100

000

Incidence

M ortality

32

Figure 1-4: World Female Lung Cancer Incidence and Mortality Rates by Region (Age standardised estimates for 2000 based on 3-5 years earlier and adjusted for increase in population8)

0

5

10

15

20

25

30

35

40

Eas

tern A

frica

Midd

le Af

rica

Nort

hern

Afric

a

Sou

thern

Afric

a

Wes

tern A

frica

Cari

bbea

n

Cen

tral A

meric

a

Sou

th Am

erica

Nort

hern

Ameri

ca

Eas

tern A

sia

Sou

th-Ea

stern

Asia

Sou

th Ce

ntral

Asia

Wes

tern A

sia

Eas

tern E

urope

Nort

hern

Europ

e

Sou

thern

Europ

e

Wes

tern E

urope

Aus

tralia

/New

Zeala

nd

Mela

nesia

Micr

ones

ia

Poly

nesia

Region

Rat

e pe

r 100

000

Incidence

Mortality

33

1.1.2. Lung Cancer in Australia

Twenty-nine percent of all male primary cancer diagnoses in Australia are of lung cancer

(Figure 1-5). It is the most common cancer diagnosis in Australian males, and in females

is second only to breast cancer (19% vs 24% of all female cancer diagnoses, Figure 1-68).

As Figure 1-7 illustrates, the rate of male deaths from lung cancer has been decreasing

since the mid 1980’s, whilst over the same period female mortality rates have increased8.

34

Figure 1-5: Australian Male Cancer Mortality Rate by Type of Cancer (Age standardised, per 100 000, estimates for 2000 based on 3-5yrs earlier and adjusted for increase in population8)

3% 4%5%

5%

16%

5%

1%

14%

0%

0%

4% 3%

4%3% 4%

29%

Buccal Cavity and Pharynx Oesophagus Stomach Rectum Intestine Pancreas Larynx Lung Prostate Thyroid Hodgkin disease Leukaemia Bladder Melanoma of skin Kidney Non-Hodgkin lymphoma

35

Figure 1-6: Australian Female Cancer Mortality Rate by Type of Cancer (Age standardised, per 100 000, estimates for 2000 based on 3-5 yrs earlier and adjusted for increase in population8)

1% 2% 3%4%

18%

7%

0%

24%

2%

4%

2%3%

3%6%

0%0%

19%

Buccal Cavity and Pharynx Oesophagus Stomach Rectum Intestine Pancreas Larynx Lung Breast Cervix uteri Thyroid Hodgkin disease Leukaemia Bladder Melanoma of skin Kidney Non-Hodgkin lymphoma

36

Figure 1-7: Australian Age Standardised Rates of Lung Cancer Mortality (Adjusted for increase in population8)

0

10

20

30

40

50

60

1968

1970

1972

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

Year

Rat

e pe

r 100

000

MaleFemale

37

In Australia, it has been estimated that the treatment cost per lung cancer patient

(excluding terminal care) averages A$14 4139. With 5553 lung cancers diagnosed in

Australia in 20008, the annual cost to the health system is tremendous. Again, the major

component of this expense is hospitalisation (42%)9. Not only does lung cancer

hospitalisation accrue direct cost in terms of treating the patient, but also by using beds,

putting added strain on the health care system as a whole.

The incidence rate of lung cancer in metropolitan Adelaide between 1986 and 1993 was

474 per year (Figure 1-1)1, with the highest incidence ratios (age and gender standardised)

in North Western, Central and outer Southern areas of metropolitan Adelaide. The overall

incidence of lung cancer is 10% lower in rural areas when compared to urban, however

there are a number of towns with elevated incidence ratios, in particular Whyalla, Port

Augusta and Wallaroo (rate ratios of 141, 132 and 131 respectively1). It has been noted

that lung cancer incidence correlates with areas of single parent and low income families,

disability pensioners, unemployment beneficiaries and male use of health service

providers1, all potential indicators of poor socioeconomic status.

1.1.3. Aetiology

Molecular research has demonstrated lung cancer to be a result of substances (lung

carcinogens) entering the lungs, and mutating and altering the function of the DNA in lung

cells. Two primary sources of lung carcinogens are cigarette smoke and industrial

processes. There is strong evidence (both epidemiological and molecular) for a causal

relationship between tobacco smoke and lung cancer through direct smoking10 11, with a

less conclusive but growing body of evidence for environmental tobacco smoke (ETS)12.

Lung carcinogenic substances have been identified in a number of occupational processes

38

and epidemiological evidence exists for an association between workers exposure to these

substances and lung cancer development13. This association is particularly strong for

“blue collar” work such as boiler making, building and construction (associated with

asbestos and particulate matter exposure), jobs involving heavy vehicles (truck driving,

forklift work, associated with polycyclic aromatic hydrocarbons and diesel exhaust), and

mining, quarry and stone work (associated with crystalline silica).

There is also a group of people with lung cancer who have not been exposed to lung

carcinogens from cigarette smoke or occupational process14. It is possible that this group

of people may have been exposed to occupational carcinogens due to emissions of waste

products from industry stacks/chimneys into the ambient air15 16. These emissions are

particularly relevant to people residing in close proximity to polluting industry. The

epidemiological evidence for a causal relationship between ambient carcinogens and lung

cancer development is weaker than that for cigarette smoking and occupational exposure,

and will be evaluated systematically in Chapter 2.

1.2. North Western Metropolitan Adelaide

The North Western suburbs of metropolitan Adelaide are comprised primarily of the Port

Adelaide statistical local area (SLA), but also include parts of the Hindmarsh and

Woodville SLA. The region identified for this research is approximately 10km by 15km,

with an 88km2 residential area and population of 100 000 (10% of metropolitan Adelaide

population).

39

The NW suburbs of Adelaide are an historical area, first settled due to the availability of

shipping ports along the Port River for the transport of goods into and out of Adelaide2.

For this reason it has also been a focal point for industrial activity, with the highest

concentration in South Australia of industry licensed to carry out “prescribed activities” by

the Environmental Protection Authority (EPA) (Personal communication, Environmental

Protection Authority of South Australia, 2003).

The SEIFA Index of Relative Socioeconomic Disadvantage is a measure used by the

Australian Bureau of Statistics to summarise demographic variables such as poverty,

income, education and housing status into one figure1. The Social Health Atlas shows that

the North West are amongst the most disadvantaged in metropolitan Adelaide. The area

also has a high concentration of public housing and unemployment1.

The people of Port Adelaide have traditionally lived as a tight knit community. A book of

oral histories from lifetime residents of the area paints a picture of a community

determined to stand by one another, particularly during the depression years17. The book

also documents the frustration residents feel towards polluting industry. Residents have

formed community groups over the previous two decades in an effort to publicise their

concerns regarding the health effects of industry in the area, particularly relating to

respiratory health. Two reports have been published by members of these groups

following residential surveys, case studies and collation of historical data18 19. Although

crude in design and primarily based on anecdotal evidence, both reports conclude that the

public of Port Adelaide need to be better informed of the quality of the air they breathe,

and of any new industrial developments or changes to licensing in the area. The groups

also believe government legislation regarding air pollution emissions should be stringently

40

enforced. Finally, the groups publications request detailed investigations be undertaken

into the health effects of residing in close proximity to industry, and subsequently living in

an area of poor air quality.

1.2.1. Lung Cancer in the North West

Data published in the South Australian Health Atlas1 indicated the NW suburbs to have

the highest incidence of lung cancer (standardised for age and gender) in metropolitan

Adelaide over the preceding 8 years (see Figure 1-1). When broken down to suburban

levels, Osborne was found to have the second highest standardised incidence ratio for lung

cancer in metropolitan Adelaide (211), more than twice that of metropolitan Adelaide as a

whole, and more than 4 times that of more affluent Eastern suburbs (Belair – 30, Burnside

– 38)1.

1.2.2. Industry in the North West

The North West of Adelaide, in particular the area surrounding the Port River, was

identified as an industrial site soon after the city of Adelaide was founded in 1836 (Figure

1-8). Initially the industry was focused on whaling (the Gulf of Saint Vincent is a

breeding passage for Southern Right Wales), wool and wheat2. In 1856 the first wool

stores were built on the corner of Lipson and Divett Streets by Elder Stirling and Co20.

The 1880’s saw a rapid increase in wool storage in the area, with some of these stores still

used today by Quality Wool2. The area’s first flour mill (Hart’s Mill, later to become the

Adelaide Milling Company) was established in 18552.

41

Figure 1-8: Aerial View of the Port River21

In the 1840’s a smelter era began. The Adelaide Smelting Company began operations in

1849 on Newcastle St at Rosewater until 18512. In 1861 the English and Australian

Copper Company built a large smelter on the bank of the Pt River (St Vincent and Mundy

Streets corner) that processed copper from mines in Burra2. When the Burra mine closed

in 1877 the smelter continued, sourcing copper from other mines, but by 1912 smelting

was phased out2. The Block 14 smelter works processed silver and lead from Broken Hill

from 1894 to 190220.

In the late 1800’s to early 1900’s a number of fertilizer companies began operations in the

North West. Three of these, Adelaide Chemical Works (formed in 1882 in Pt Adelaide),

Adelaide Chemical and Fertilizer Company (a sulphuric acid plant established in 1900 in

Pt Adelaide, known as TOP post 1906) and SA Fertilizer Company (1913, Birkenhead,

known as Cresco Fertilizer Company after 1920) still exist today under the banner of

Adelaide Wallaroo Fertilizers22.

42

In the early 1900’s the area was known for its ship building, with the first ship built at

Osborne launched in 192022. A paint manufacturer became operational in 1906 on Lipson

St, Pt Adelaide, which made lead based paint until the 1960’s, when it was renamed Dulux

and became involved in car duco paint production22.

The Pt Adelaide region supplied much of Adelaide with its first gas from gasworks at

Rosewater (operational 1866 to the 1920’s), Peterhead (1979) and Osborne (1928 to 1930,

and 1939 to 197922). By 1969 the states gas was supplied from Moomba so plants in the

North West were shut down (other than Osborne which continued to supply gas to nearby

industry)22. It was also a site for electricity generation, with the states first power station

operational in Osborne in 192322. An additional plant was built at the site in 1938,

however both ceased operation when the Torrens Island Power Station (which remains in

operation today) began generating power in 1967(Figure 1-9)22.

43

Figure 1-9: The Torrens Island Power Station23

A number of factories manufacturing building products have been situated in close

proximity to the Port River. In 1891 a cement mix producer (CSR) began operations in

Glanville and, other than an interruption due to an extensive fire in 1926, it remained

working until 199120. Adelaide Brighton Cement, one of the most recognisable industrial

buildings in the region today, began manufacturing cement products in 1914 at its

Birkenhead plant (Figure 1-10)20. ICI (now known as Penrice Soda Products) began

manufacturing soda ash in 1940 and continues today at its Osborne site2. Asbestos

Cement Ltd (part of the James Hardies Victorian company) manufactured asbestos sheets,

roofing and pipes under the brand name Asbestolite from 1941 until it was phased out in

the 1980’s24.

44

Figure 1-10: Aerial View of Adelaide Brighton Cement25

Whilst industry in the Pt Adelaide and Lefevre Peninsula region developed quickly, by the

mid 1900’s there were 2 other key industrial regions in the North West suburbs; Finsbury

and Hendon. Finsbury began its industrial activity in 1941 manufacturing shell cases and

fuses (munitions) for the war, under the name The Cheltenham Works in Woodville

North26. By 1946 the factories were leased by private companies for engineering,

automotive and whitegoods production (this included Kelvinator, Apac Industries,

Firestone Tyre and Rubber Company), a number of which are still operational today26.

Hendon was also involved with munitions production, but after the war in 1947 became a

much smaller industrial area operated wholly by Phillips Electrical Industries26.

45

Today there are 205 industries licensed to carry out ‘prescribed activities’ (permission to

release a range of emissions into the air) in the North West Adelaide Lung Cancer Study

geographic area. This is 33% of all licensed industry in metropolitan Adelaide, in an area

where 10% of the population live. Many of these industries operate in close proximity to

residential homes as is shown in Figure 1-10 where homes are directly across the road

from industry. The majority of these industries undertake air-polluting activities

(Environmental Protection Authority (EPA)). Licensed industry are allowed to carry out

a variety of polluting activities and are required to regularly report their emissions to the

South Australian EPA. As per the industrial history above, the majority of industry is

clustered around the Port River. However, also as described, many of the industries

operating in the region have since closed. In addition, clean air regulations introduced in

1972 and changes to Australian design rules in the 1970’s27 28mean it is likely that

historical air quality was poorer than that of today.

Table 1-2 lists major industries located in the North West area, the proximity to which will

be used to assess the residential exposure of study participants. Each was identified after

research into the industrial history of the region, and was selected due to it being

operational at the time relevant for exposures relating to contemporary lung cancer cases

(15 to 30 years latency period29), and the high likelihood of each to have emitted lung

carcinogens during its operations (as determined by an occupational hygiene panel

comprised of three occupational hygienists with specific historical and contemporary

knowledge of metropolitan Adelaide, the panel will be explained in more detail in the

Methods Chapter).

46

Table 1-2: Key Industry Identified as having the Potential to Emit Lung Carcinogens, and Operational in the Study Area (North West Suburbs of Adelaide) in the period 1970 to 2000 Name Location Year

Established

Year

Closed

Type of industry Potential Lung

Carcinogens

Emitted

Additional Information Reference

Adelaide

Brighton

Cement

Charles St,

Birkenhead

1914 N/A* Cement production Crystalline silica

PM2.5

Originally named

Adelaide Cement

Company, renamed in

1971

20 30

ICI/Penrice

Soda

Products

Osborne 1940 N/A* Soda products plant

(produced soda ash)

Crystalline silica

PM2.5

Renamed Penrice Soda

Products in 1987

2 31

CSR Glanville 1891 N/A* Mineral building

product manufacture

Crystalline silica

PM2.5

Fire in 1926 destroyed

much of the plant, it

was rebuilt soon after

20 32

47

Name Location Year

Established

Year

Closed


Carcinogens

Emitted


Torrens

Island

Power

Station

Torrens

Island

1967 N/A* Electricity

generation

PAH Additional 3 units

operational 1971

22

James

Hardies –

Asbestos

Cement Pty

Ltd

Birkenhead 1941 Phased

out in

early

1980’s

Asbestos product

manufacture (sheets,

roofing, pipes)

asbestos Initially owned jointly

with Wunderlich Ltd

who were bought out in

1960. Product brand

name was Asbestolite.

24

48

Name Location Year

Established

Year

Closed


Carcinogens

Emitted


Finsbury

Industrial

suburb

Woodville

North

1941 N/A* Prior to 1945 a

government

munitions factory,

post 1946 area was

private leased and

home to a cluster of

industry including

engineering,

automotive,

household appliance

& electrical goods

factories

Diesel exhaust,

PAH, PM2.5

Initially known as “The

Cheltenham Works”.

1945 change in industry

type – see industry

types column

33 26

* N/A – not applicable as industry is still operational

49

1.2.3. Ambient Air Quality in the NW

In the past decade ambient air quality monitoring has been regularly carried out in the

North Western suburbs by the South Australian EPA (usually on a 6 day cycle)34.

Monitoring stations for PM10 are located in Osborne and Port Adelaide. The National

Environmental Protection Measure (NEPM) guideline indicates that more than 5 days

per year of 24hr PM10 exceeding 50ug/m3 is unacceptable35. Between 1993 and

1999 the NEPM standard was never exceeded in Pt Adelaide, as opposed to Osborne

where the standard was exceeded for 5 days in each of 1990 and 1993, and for 6 days

in each of 1991, 1994, 1998 and 199934. Other air pollutants have not been

consistently monitored in the North West.

The EPA also has a van used for “hot-spot” monitoring. The location of this van is

rotated depending on government and community concerns, complaints and requests.

In 1996 the EPA van was rotated between 3 sites in the North Western suburbs for a

total of 18 weeks (Site 1 – residential area, Site 2 – area containing cement works,

Site 3 – area containing a soda plant and power generation plant). This monitoring

was carried out in conjunction with the cross sectional survey discussed previously3.

Nitrogen dioxide, sulphur dioxide and ozone 1 hour concentrations did not vary

significantly between the 3 locations, and did not exceed NHMRC ambient air quality

guidelines3.

Whilst some monitoring has been carried out in the North West both regularly and

sporadically, the resulting data can not be used to assess the residential exposure of

incident lung cancer cases due to the lung cancer latency period of 15 to 30 years29.

In addition, existing monitoring data has little relevance as it has not specifically

50

targeted potential lung carcinogens, nor has its location had a specific health focus.

Given the ongoing collocation of a diverse range of industry and residential homes it

is important, and relevant to a study of incident lung cancer in the region, to quantify

current levels of airborne lung carcinogens in the area to be used as an indicator of

future respiratory health risk.

51

2. Chapter 2 Review of the Literature

Chapter 1 described the high rate of lung cancer in the North West of metropolitan

Adelaide, an area containing residential homes in close proximity to industry. Before

conducting research to investigate the relationship between lung cancer and air pollution

from industry, it is important to determine what other evidence for this relationship exists

both in Australia and internationally. This chapter provides an overview of how

substances are able to induce lung cancer, the evidence for air pollutants to be

carcinogenic and the likelihood of these pollutants to be present in the North West of

Adelaide. It also includes a systematic review investigating whether evidence of a causal

relationship between air pollution and lung cancer can be concluded from previously

published epidemiological studies (as published in Respirology36), and an evaluation of

Australian research investigating lung cancer and air pollution. Finally, the aims,

objectives and hypothesis for this study are presented.

52

2.1. Lung Cancer Histology

Lung cancer development results from a multistage process of mutations and

morphological changes in the cells of the lung. When inhaled lung carcinogens are

metabolised to become reactive carcinogenic metabolites. These metabolites are able to

interact with and bind to DNA to form mutagenic DNA adducts7. Mutations leading to

cancerous cells occur in two broadly classified types of genes, proto-oncogenes, and

tumour suppressor genes7. Proto-oncogenes are a group of genes that promote cell growth

and replication by producing proteins that initiate metabolic or transcriptional activity in

the cell. The ras and myc families of proto-oncogenes have both been associated with

lung cancer development. Tumour suppressor genes are those that regulate and restrain

cell growth and replication by producing proteins that inhibit metabolic or transcriptional

activity7. Mutations in p53 (responsible for the production of a phosphoprotein that

arrests the G1 phase of the cell cycle when DNA checking and repair occurs) and

retinoblastoma (rb, responsible for production of a nuclear phosphoprotein involved with

the cell cycle) tumour suppressor genes have been associated with lung cancer. Lung

carcinogens are able to mutate proto-oncogenes or tumour suppressor genes to initiate

uninhibited cell growth and proliferation, while preventing apoptosis (programmed cell

death), therefore promoting tumour development in the cellular tissue of the lung7.

53

2.1.1. Lung Cancer Classification

When lung cancer is diagnosed it is classified by the cell type and level of differentiation.

This level of diagnosis is usually obtained by tumour biopsy and assists in determining the

treatment and prognosis of the patient. Associations have been identified between specific

types of lung cancer and sources of carcinogens (for example smoking with squamous cell

carcinoma, and occupational exposures with adenocarcinomas)6. Table 2-1 describes the

features of each cell type. Mixed tumours are also possible, but are usually classified

according to the most dominant cell type in the mixture (as it most closely predicts patient

outcome) and are rarely diagnosed except in autopsy.

Cellular differentiation is a measure of the distortion of tumour cells when compared to a

non-cancerous cell of the same type. Two of the levels of differentiation are illustrated in

Figure 2-1. A decrease in cellular differentiation indicates a highly developed tumour and

hence a poor prognosis for the patient.

54

Table 2-1: Features of each Lung Cancer Cell Type

Adapted from Mosby’s Crash Course –Respiratory Systems6

Cell Types

Non-small-cell tumours

Squamous cell

tumour

Adeno-

carcinoma

Large cell Small cell

Relative incidence

(%)

52 13 5 30

Male (M) to

Female (F) ratio

M>F F>M M>F M>F

Location Hilar Peripheral Peripheral/

central

Hilar

Smoking

association

High Low High Very High

Growth rate Slow Medium Rapid Very Rapid

Metastasis Late Intermediate Early Very Early

55

Figure 2-1: Two Levels of Tumour Differentiation

These high power histological photos with haematoxylin and eosin stain were provided by

the Department of Pathology, University of Adelaide.

a) Well differentiated squamous cell carcinoma. Note the islands of large tumour cells

with large nuclei (blue/purple), abundant eosinophilic (pink) cytoplasm and areas of

keratinisation (deep pink round area).

b) Highly undifferentiated (or anaplastic) squamous cell carcinoma. Note the large

tumour cells with large nuclei (blue/purple) and relatively little cytoplasm.

56

2.2. Lung Carcinogen Classifications

Substances are classified as carcinogenic based on evidence from molecular, animal and

human research. Classifications from the International Agency for Research on Cancer

(IARC) are convention internationally (Table 2-2)37.

Table 2-2: Carcinogen Classifications Employed by IARC37

Category Description

Group 1 The agent or mixture is carcinogenic to humans

Group 2A The agent or mixture is probably carcinogenic to humans

Group 2B The agent or mixture is possibly carcinogenic to humans

Group 3 The agent or mixture is not able to be classified according to its carcinogenicity

Group 4 The agent or mixture is probably not carcinogenic to humans

2.2.1. Lung Carcinogens

For this study we are interested in substances known to be (Group 1) or probably (Group

2A) carcinogenic to the lung or respiratory tract of humans. Carcinogens in these

categories were selected to reduce contamination of exposure estimates with substances

not likely to be carcinogenic, and because this study did not aim to identify new

respiratory carcinogens. Table 2-3 lists lung carcinogens assigned one of these

classifications and their sources (including potential sources in the North Western suburbs

of Adelaide).

57

Table 2-3: Known (1) or Probable (2a) Respiratory Carcinogens and their Potential

Sources38 39

Substance Category Source NW Adelaide potential

source

Asbestos 1 Construction work &

maintenance, mechanical

brake lining

Abandoned asbestos

cement manufacturing

factory

Crystalline

silica

1 Mining, masonry,

stonework, concrete &

gypsum, pottery

Cement manufacturer

Polycyclic

Aromatic

Hydrocarbons

2a Furnaces, aluminium

industry, bitumen & asphalt,

residential heating

Heavy vehicle traffic,

Power station, Light

industry

Diesel exhaust 2a Trucking, combustion Industrial vehicle traffic

Particulate

matter

* Welding, building products

manufacture

Mineral building product

manufacturer, light

industry

Formaldehyde 2a# Adhesive in manufacture of

particle board, fibreboard &

plywood, disinfectant and

preservative

Industrial vehicles

Asbestos cement

manufacturer (converted to

fibreboard in the 1980’s)

58

Substance Category Source NW Adelaide potential

source

Arsenic 1 Alloying agent, herbicides,

insecticides, wood

preservative, mining

Historically – pesticide

manufacturer and timber

mill

Beryllium 1 Mining, refining and

manufacture of ceramics,

electronic and aerospace

equipment

No

Nickel 1 Production of stainless steel,

alloys, electroplating and

battery manufacture

No

Cadmium 1 Electroplating, some plastics

manufacturer, alloys and

electrodes in batteries

No

Chromium 6 1 Production of stainless steel,

chrome alloys and welding

Stainless steel welding in

some industries

Radionuclides

(Radon)

1 Uranium mining and

processing

No

* - Whilst at the time of identifying carcinogens it was not identified as carcinogenic itself,

components of Particulate Matter such as welding fumes and wood dust have been

classified as carcinogenic, and it is able to act as an airborne carrier for a variety of

substances including carcinogens # - Formaldehyde is a respiratory carcinogen rather than being specifically related to lung

cancer

59

2.3. The Origins of the Association between Air Pollution and Lung Cancer

Descriptive epidemiological studies specifically investigating a potential relationship

between lung cancer and air pollution emerged in the literature in the 1950’s. Initial

studies were ecological and compared lung cancer rates between rural and urban

populations, immigrants and non-immigrants and industrial and non-industrial regions15.

Rural versus urban studies found smoking gradients of lung cancer were steeper in

industrial urban areas compared to rural. Studies have found that the rates of lung cancer

in migrants fell somewhere between the rates in their country of origin and their new

country. In the latter studies, an increased lung cancer rate in migrants when in their new

country may be attributed to occupational exposure (due to a higher proportion of

migrants employed in blue collar work). Due to the limitations of the ecological study

design, particularly a lack of confounder adjustment, such studies require cautious

interpretation today. In 1978 Sir Richard Doll summarised that preliminary evidence for

an association between lung cancer and ambient carcinogens did exist, and suggested a

potential interaction effect between smoking and ambient carcinogens40.

2.4. A review of the Epidemiological Evidence for a Causal Relationship between

Environmental Exposure to Carcinogens (Air Pollution) and Lung Cancer

The aim of the following section is to systematically evaluate the strength of evidence

presented in the medical literature in the past two decades for a causal relationship

between exposure to air pollution and lung cancer development by application of the

Bradford Hill criteria for causality41.

Two previous reviews in 1983 and 1990 concluded that the effect of air pollution on lung

cancer is greater than zero, but the epidemiological evidence was weak due to poor

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confounder adjustment and studies of a descriptive nature15 16. The majority of studies at

the time of publication for these reviews were ecological, both reviews briefly assessed the

evidence from these studies, concluding that they demonstrated an association between

lung cancer and air pollution, but did not adjust for the confounding nature of cigarette

smoking. Methods of exposure assessment (both air pollution and for cigarette smoking

and occupation as confounders) were criticised for lacking adequate detail. These reviews

also highlight the inherent heterogeneity of both the air pollution exposure measurements

and study outcomes.

In this review, “air pollution” is the generic term used to describe the risk factor of

ambient exposure to potentially carcinogenic airborne substances. In the results section

the methods used by each paper to quantify air pollution will be described. In addition

“lung cancer” refers to the study health outcome of either primary lung cancer mortality or

incidence, as diagnosed by a registered doctor or at autopsy.

2.4.1. Literature Review Methodology

A structured literature search was undertaken on MEDLINE and EMBASE databases

using the following key words (EMBASE M-tags numbers in brackets): lung neoplasm

(306) AND epidemiology (400) AND human (888) AND air pollution AND NOT molec*.

A handsearch of reference lists was also undertaken.

Literature identified in the primary search was then culled based on the following

inclusion criteria; post 1982 case control or cohort study that had described its study

population, measured ambient environmental factors and considered the confounding

effects of both tobacco smoke and occupational exposure. This criteria ensured that the

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final set of studies were of an analytical design, and had all attempted to adjust for

Documents

The association between air pollution and lung cancer in ...€¦ · The association between air pollution and lung cancer in the North West of Adelaide: a case control study and